This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it relates to non-peptide GnRH antagonists or agonists and to their preparation. These non-peptide GnRH agents have advantageous physical, chemical and biological properties, and are useful medicaments for diseases or conditions mediated by modulation of the pituitary-gonadal axis. The compounds of the invention avoid the degradation and biodistribution problems of peptide agents.
The release of a hormone (a biochemical substance that is produced by a specific cell or tissue and causes a change or an activity in a cell or tissue located elsewhere in the organism) by the anterior lobe of the pituitary gland (which is located at the base of the brain and secretes hormones related to growth and sexual development) usually requires the prior release of another class of hormones produced by the hypothalamus (a structure in the lower part of the brain that is connected to and controls the pituitary gland). One of the hypothalamic hormones acts as a factor that triggers the release of the gonadotropic hormones, particularly LH (luteinizing hormone, which is the pituitary hormone that causes the testicles in men and ovaries in women to manufacture sex hormones) and FSH (follicle-stimulating hormone, which is the pituitary hormone that stimulates follicle growth in women and sperm formation in men). This hormone is referred to herein as xe2x80x9cGnRHxe2x80x9d (gonadotropin-releasing hormone) and/or xe2x80x9cLH-RHxe2x80x9d (luteinizing hormone-releasing hormone). GnRH is a decapeptide hormone produced by the arcuate nuclei of the hypothalamus (an arcuate nucleus is any of the cellular masses in the thalamus, hypothalamus, or medulla oblongata) that controls the pituitary gland""s production and release of gonadotropins (hormones including FSH and LH that are produced by the pituitary gland that control reproductive function). GnRH (LH-RH) may be represented by the sequence pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 or, in the single-letter code designation, pyro-EHWSYGLRPG-NH2. GnRH acts on high-affinity pituitary receptors to stimulate LH and FSH production and release.
The pituitary response to GnRH varies greatly throughout life. GnRH and the gonadotropins first appear in the fetus at about ten weeks of gestation. The sensitivity to GnRH declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to (GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases, and pulsatile LH secretion ensues. Later in puberty and throughout the reproductive years, pulsations occur throughout the day, with LH responsiveness being greater than that of FSH. After menopause, FSH and LH concentrations rise, and postmenopausal FSH levels are higher than those of LH.
Pulsatile GnRH release results in pulsatile LH and FSH release. However, sustained infusion of GnRH and its analogs results in inhibition of LH and FSH release. This phenomenon has been utilized in the successful treatment of gonadotropin-mediated precocious puberty by the sustained administration of LH-RH or its analogs. Conversely, in people with GnRH deficiency, the pulsatile administration of LH-RH can restore a normal menstrual cycle or normal sperm and testosterone production.
GnRH agonists, which are compounds that stimulate the pituitary gland to release or modulate FSH and LH, have been the mode of choice for treating sex-steroid-dependent pathophysiologies, owing to the limited number of suitable antagonists available for clinical evaluation. GnRH antagonists, which are compounds that suppress the pituitary gland from releasing FSH and LH, however, are now being considered.
GnRH antagonists may be useful for suppressing gonadotropin secretions and preventing ovulation in female mammals. GnRH antagonists have been investigated for contraception and for regulating conception periods, as well as for treating infertility, for controlling induction of ovulation in women with chronic anovulation, and for in vitro fertilization. GnRH antagonists may also be useful for the treatment of precocious puberty, endometriosis (including endometriosis with pain), acne, amenorrhea (e.g., secondary amenorrhea), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), and breast and gynecological cancers. GnRH antagonists may also be useful in the symptomatic relief of premenstrual syndrome (PMS). They may also be used to treat ovarian hyperandrogenism and hirsutism. Antagonists have also been found useful to regulate the secretion of gonadotropins in male mammals and may be employed to arrest spermatogenesis, e.g., as male contraceptives for treatment of male sex offenders, and for treatment of prostatic hypertrophy. More specifically, GnRH antagonists may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors, and for the control of the timing of ovulation for in vitro fertilization. GnRH antagonists may also be used to treat patients having illnesses, such as AIDS, wherein stimulation of the thymus to produce T-cells would be beneficial. All such uses relate to the ability of the GnRH antagonist to block the activity of GnRH.
Heretofore, available GnRH antagonists have primarily been peptide analogs of GnRH. See, e.g., International Publication No. WO 93/03058. Peptide antagonists of peptide hormones are often quite potent; however, the use of peptide antagonists is typically associated with problems because peptides are degraded by physiological enzymes and often poorly distributed within the organism being treated. Thus, they have limited effectiveness as drugs. Consequently, there presently exists a need for non-peptide antagonists of the peptide hormone GnRH.
An object of the invention is therefore to provide non-peptide compounds that are GnRH agents (agonists or antagonists) that bind to GnRH receptors and thus modulate activity, especially those that are potent GnRH antagonists. Another object of the invention is to provide effective therapies for individuals needing therapeutic regulation of GnRH and to provide methods for treating diseases and conditions mediated by GnRH regulation.
Such objects have been achieved by the non-peptide GnRH compounds of the invention, which are useful as pharmaceuticals for indications mediated by GnRH regulation. The inventive compounds are pharmaceutically advantageous over peptide compounds since they provide better biodistribution and tolerance to degradation by physiological enzymes. The invention further provides methods of synthesizing the compounds as well as intermediate compounds useful for making the compounds.
GnRH agents of the invention are of the general Formula I: 
wherein:
Z is a group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, and C(O)OR, where R is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and where the total number of carbon atoms present in Z, not including optional substituents, ranges from 1 to 12;
Y is a lipophilic group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, where the total number of carbon atoms present in Y, not including optional substituents, ranges from 6 to 20;
X1 is a structural unit, or spacer, used to connect the CH2NC(O), X2, Y, and Z functional units in 3-dimensional space, that is selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl such that the atom count in the chain portion of the unit linking the central nitrogen (the N atom in Formula I is referred to as the xe2x80x9ccentral nitrogenxe2x80x9d to avoid confusion with any other nitrogen-bearing substituents) to X2 ranges from 3 to 8, preferably from 4 to 6; and
X2 is a basic group having a pKa greater than about 8 that is preferably selected from substituted and unsubstituted guanidinyl, amidinyl, acylamidinyl, azetidinyl, and amino.
In addition to compounds of the Formula I, GnRH agents of the invention include pharmaceutically acceptable salts, multimeric forms, prodrugs, and active metabolites of compounds of the Formula I. Such non-peptide agents are pharmaceutically advantageous over peptide agents since they provide better biodistribution and tolerance to degradation by physiological enzymes.
The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a GnRH agent of the invention in combination with a pharmaceutically acceptable carrier or diluent. Moreover, the invention relates to methods for regulating the secretion of gonadotropins in mammals, comprising administering therapeutically effective amounts of GnRH agents of the invention.
The invention further relates to processes for synthesizing the compounds as well as to intermediate compounds useful for making the compounds. Intermediate compounds uses for making compounds of the Formula I are those encompassed by the following Formulae II, III, and IV: 
wherein:
j is 1 or 2;
k is 1,2,3,4 or 5;
R8 is H or substituted or unsubstituted lower alkyl;
R9 is H or substituted or unsubstituted lower alkyl, CN, NO2 or CO2R1;
R10 is H or substituted or unsubstituted lower alkyl, CH2OR1, (CH2)pOR1, CO2R1, or (CH2)pC(O)R2, where p is an integer from 1 to 6, and R2 is H, OR1, SR1, N(R1)2, or C(R1)3;
R11 is H or substituted or unsubstituted lower alkyl, CH2O-phenyl, CH2O-benzyl, phenyl, or benzyl;
or any two of R8, R9, R10, and R11 (R8 and R9, or R8 and R11, or R8 and R10, or R9 and R10, or R9 and R11, or R10 and R11) taken together form a 5- or 6-membered heterocycle;
and where each R1 is independently selected from H and substituted or unsubstituted lower alkyl, O-lower alkyl, and S-lower alkyl.
Other features, objects, and advantages of the invention will become apparent from the following detailed description of the invention and its preferred embodiments.